ER-phagy Activation by AMFR Attenuates Cardiac Fibrosis Post-Myocardial Infarction via mTORC1 Pathway

Abstract

Progressive cardiac fibrosis post myocardial infarction (MI) drives pathological remodeling and heart failure, yet the role of endoplasmic reticulum-selective autophagy (ER-phagy) in this process remains unclear. Autocrine Motility Factor Receptor (AMFR) is a recently identified ER-phagy regulator, whose function under myocardial pathology remains poorly understood. Here, it is found that FAM134B-mediated ER-phagy activity is elevated in fibrotic mouse heart tissues post-MI and in cardiac fibroblasts stimulated by TGF-β1. AMFR knockout in mice aggravated cardiac fibrosis post-MI and worsened cardiac function, with scRNA-seq analysis demonstrating that AMFR-null cardiac fibroblasts exhibit a myofibroblast phenotype. Simultaneously, AMFR overexpression in cardiac fibroblasts reduces the expression of profibrogenic proteins in response to TGF-β1 stimulation. AMFR regulates ER-phagy flux and turnover of FAM134B, which leads to the suppression of cardiac fibroblasts activation. Mechanistically, AMFR catalyzed K27-linked (predominant) and K33-linked ubiquitination of FAM134B and enhanced ER-phagy flux, thereby inhibiting the phosphorylation of mTORC1 downstream targets such as S6K1 and 4E-BP. These findings highlight the therapeutic potential of AMFR-driven ER-phagy in suppressing cardiac fibrosis post-MI.